SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation.
SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation.
复制标题
SENP 5通过H2AZ去SUMO化促进结直肠癌细胞中同源重组介导的DNA损伤修复
DOI：
10.1186/s13046-023-02789-9
复制
发表时间：
2023-09-08
影响因子：
11.3
通讯作者：
Yang, Yanyong
中科院分区：
文献类型：
--
作者：
Liu, Tingting;Wang, Hang;Chen, Yuanyuan;Wan, Zhijie;Du, Zhipeng;Shen, Hui;Yu, Yue;Ma, Shengzhe;Xu, Ying;Li, Zhuqing;Yu, Nanxi;Zhang, Fangxiao;Cao, Kun;Cai, Jianming;Zhang, Wei;Gao, Fu;Yang, Yanyong
新辅助放疗已被用作结直肠癌（CRC）的标准治疗。然而，放射治疗抵抗往往导致治疗失败。放射抗性基因的发现将为联合治疗和预后标记提供新的靶点。通过对放射治疗敏感或耐药的结直肠癌患者的高含量筛选和组织芯片，我们发现了一个有效的耐药基因SUMO特异性肽酶5（SENP 5）。采用CCK-8、克隆形成、彗星试验、免疫荧光、流式细胞术分析细胞凋亡和细胞周期等方法研究SENP 5对放射敏感性的影响。采用SUMO-蛋白质组学质谱结合免疫共沉淀技术鉴定SENP 5的靶点。采用患者源性类器官（PDO）和异种移植物（PDX）模型探索临床应用的可能性。我们通过高含量筛选和结直肠癌患者组织阵列分析，将SENP 5鉴定为一个有效的抗辐射基因。SENP 5高表达的患者对放疗的抵抗力增加。体外和体内实验证明，SENP 5敲低显著增加了CRC细胞的放射敏感性。SENP 5在DNA损伤修复过程中起着重要的作用，并依赖于同源重组（HR）。通过SUMO质谱分析，我们将H2 AZ表征为SENP 5的去SUMO化底物，并描绘了H2 AZ在HR修复和癌症抵抗中的SUMO化平衡。通过使用PDO和PDX模型，我们发现靶向SENP 5显著增加了放射治疗的疗效。我们的研究结果揭示了SENP 5在HR介导的DNA损伤修复和癌症抗性中的新作用，其可作为有效的预后标记物和癌症放射治疗的干预靶点。在线版本包含补充材料，可通过10.1186/s13046-023-02789-9获得。
Neoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers. Through high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application. We identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy. Our findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy. The online version contains supplementary material available at 10.1186/s13046-023-02789-9.
登录
查看更多内容
影响因子：
11.5
作者：
Durinikova, Erika;Reilly, Nicole M.;Buzo, Kristi;Mariella, Elisa;Chila, Rosaria;Lorenzato, Annalisa;Dias, Joao M. L.;Grasso, Gaia;Pisati, Federica;Lamba, Simona;Corti, Giorgio;Degasperi, Andrea;Cancelliere, Carlotta;Mauri, Gianluca;Andrei, Pietro;Linnebacher, Michael;Marsoni, Silvia;Siena, Salvatore;Sartore-Bianchi, Andrea;Nik-Zainal, Serena;Di Nicolantonio, Federica;Bardelli, Alberto;Arena, Sabrina
通讯作者：
Arena, Sabrina
影响因子：
10.5
作者：
Garvin, Alexander J.;Walker, Alexandra K.;Morris, Joanna R.
通讯作者：
Morris, Joanna R.
影响因子：
3.8
作者：
Li, Zhiqing;Mon, Hiroaki;Kusakabe, Takahiro
通讯作者：
Kusakabe, Takahiro
影响因子：
10.5
作者：
Leung JW;Makharashvili N;Agarwal P;Chiu LY;Pourpre R;Cammarata MB;Cannon JR;Sherker A;Durocher D;Brodbelt JS;Paull TT;Miller KM
通讯作者：
Miller KM
影响因子：
4.7
作者：
Mekonnen, Negesse;Yang, Hobin;Shin, Young Kee
通讯作者：
Shin, Young Kee